The heart is a muscle, which pumps the blood in the circulation by contracting 1-3 times per second. The heartbeat is caused by simultaneous contraction of the individual cardiac muscle cells (cardiac myocytes). The synchronization of the cellular contraction is governed by the electrical cardiac impulse (the cardiac action potential), which is generated in the pacemaker cells of the sine node and spreads rapidly over the heart through a specific conduction system.
Disturbances in the generation of the impulse and the conduction of impulse may occur either as a consequence of a disease, a drug treatment or electrolyte imbalances. Such disturbances in the impulse are called arrhythmia or dysrythmia and they may lead to unease, emboli, syncope or sudden death.
At a molecular level a group of proteins called ion channels underlie the electrical events in the heart since they are able to conduct electrical currents across the cell membrane. Different types of ion channels are thus instrumental in the generation and conduction of the cardiac action potential, in the regulation of the heart rate by the autonomic nervous system, and in the contractile process in the individual heart cells. The different types of ion channels are therefore good targets for anti-arrhythmic cardiac drugs, and many anti-arrhythmic drugs on the market do exert their effect by interacting with ion channels.
One of the ion channels responsible for the termination of the cardiac action potential is the human ERG1 channel (Human Ether-a-go-go Related Gene channel, HERG1 channel), which is selective for permeation of potassium ions. Block of this channel caused by drugs or genetic dysfunction may lead to arrhythmia.
A number of drugs have been shown to block the ERG channels, including compounds as diverse as anti-psychotics, anti-depressants, anti-histamines and anti-biotics. Several of these drugs have been withdrawn from the market, or put on prescription, within recent years due to pro-arrhythmic effects. Pharmacological block of HERG1 channels leads to a prolongation of the cardiac action potential and a reduced potassium conductance during the repolarisation and resting phase of the action potential. The prolonged action potential is reflected in the ECG as an increased distance between the Q and T waves, and the condition is called acquired Long QT Syndrome. Patients being treated with HERG1 blocking drugs can develop serious ventricular tachy-arrhythmia called torsade-des-pointes, which may eventually lead to syncope and possibly cardiac arrest.
HERG1 channels are targets for a number of genetic mutations giving rise to inherited Long QT Syndrome. These patients also develop serious arrhythmias of the torsade-des-pointes type as well as a number of other arrhythmias including brady-arrhythmias. The patients are currently often treated with adrenergic beta-receptor blockers or pacemakers possibly with intracardial defibrillators (ICD).
Most of the existing anti-arrhythmic drugs on the market were developed before their molecular target was known. However, for many of them their molecular target has later been shown to be an ion channel.
Anti-arrhythmic drugs are usually divided into four main classes.
Class 1 compounds all block the cardiac voltage-dependent sodium channel. Some class 1 compounds do have additional effects influencing the cardiac action potential being the basis for a further subdivision into three subclasses:
Class 1A compounds are sodium channel blockers such as Quinidine or Disopyramid, which prolong the action potential.
Class 1B compounds are sodium channel blockers such as Lidocaine, Mexiletin or Phenytoin, which shorten the action potential.
Class 1C compounds are sodium channel blockers such as Flecainid or Propafenon, which do not change the action potential duration.
Class 1 compounds interact with the sodium channel during its open or inactivated state and are dissociated from the channels during its closed state (during diastole). The rate of dissociation determines whether they show a frequency-dependent channel block. Some of the class 1 compounds also block subtypes of potassium or calcium permeable channels in addition to their sodium channel blocking effect.
Class 2 compounds are β-adrenoceptor blockers and include drugs like Atenolol, Metoprolol, Timolol or Propranolol. β-adrenoceptor blockers can be selective for cardiac β1-receptors or have affinity for β1- as well as β2-receptors. Some of the compounds have an intrinsic β-stimulating effect too.
Class 3 compounds are potassium channel blockers such as Amiodaron, which prolong the action potential by delaying repolarisation of the action potential through block of potassium channels. Class 3 compounds show lack of effects in many patients and may even be pro-arrhythmic, probably due to the destabilising effect of the reduced potassium current.
Class 4 compounds are blockers of L-type calcium channels such as Verapamil.
In addition to the compounds allocated to those four classes, Digoxin and Adenosin also find use in the treatment of arrhythmia.
WO 96/28537 describes long QT genes and methods for diagnosing or preventing the occurrence of Long QT Syndrome. WO 00/06772 describes mutations in and genomic structure of HERG1, a Long QT Syndrome gene. WO 02/42417 describes a new human ERG (HERG2) channel. WO 02/42735 describes a method of identifying HERG channel inhibitors. However, the use of HERG1 channel openers for the treatment of cardiac arrhythmias has never been suggested.
Moreover, WO 94/22807, WO 96/25157, WO 97/45400, WO 97/45111, WO 98/47879, WO 00/24707 and WO 2004/022529 describe urea derivatives useful as potassium channel modulators or chloride channel blockers, but an effect on HERG1 channels have not been reported with these compounds.